The limited capability of the central nervous system (CNS) to repair itself after damage remains a significant challenge for basic and clinical sciences. Among the approaches for restoration of lost neuronal function, the use of embryonic stem (ES) cells as donor source for neural transplantation is increasingly receiving attention. Yet, there is a surprising shortage of data demonstrating functional characteristics of ES cell-derived progeny incorporating into damaged CNS circuitries. In recent studies, we have determined basic morphological and functional attributes of ES cell-derived astrocytes and neurons integrating into normal hippocampal tissue. In this grant application we propose the anatomical and functional evaluation of ES cell-derived neural precursors (ESNPs) grafted into the structurally impaired hippocampal formation. Although in vivo studies are planned for data confirmation, our experimental approach primarily involves transplantation and electrophysiological characterization of fluorescent-labeled ESNPs in organotypic hippocampal slice cultures (HSCs). HSCs will be derived from two animal models with severe neuronal cell loss affecting and impairing the hippocampal formation: the flathead mutant and sublethally irradiated Wistar rats. The rationale for choosing the animal models was that, although etiologically different, they both have in common a loss of a significant amount of neurons in the hippocampus. The flathead mutants are affected from severe impairments in the generation of dentate gyrus granule cells and interneurons, due to an inherited loss of the citron kinase gene. Wistar rats, which receive external brain irradiation in early postnatal life stages show a significant loss of granule cells, representing a somewhat acquired form of injury. As functional integration may depend on both, the environmental characteristics of the recipient CNS structure, and on the nature of engrafted cells, we will additionally explore the need of defining suitable donor cell populations for successful neural circuitry integration. The synaptic integration of ESNP-derived neurons and their functional interactions with disrupted or degenerated host circuitries may serve as a novel experimental platform for the development of neural transplantation strategies for a variety of neurological diseases.